Abstract
The inflammatory response following spinal cord injury (SCI) involves the activation of resident microglia and the infiltration of macrophages. Macrophages and microglia can be polarized into the classically activated proinflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 phenotype. Programmed cell death 1 (PD-1) is a critical immune inhibitory receptor involved in innate and adaptive immune responses. However, whether PD-1 is involved in the modulation of macrophage/microglial polarization is unknown. In this study, the mRNA levels of pd1 gradually increased after SCI, and PD-1 protein was found in macrophages/microglia in injured spinal cord sections. PD-1 knockout (KO) mice showed poor locomotor recovery after spinal cord crushing compared with wild-type mice. M1-type macrophages/microglia accumulated in greater numbers in the injured spinal cord of PD-1-KO mice. Under polarized stimulation, induced expression of PD-1 occurred in cultured macrophages and microglia. PD-1 suppressed M1 polarization by reducing the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and promoted M2 polarization by increasing STAT6 phosphorylation. In PD-1-KO mice, the M1 response was enhanced via the activation of STAT1 and nuclear factor-kappa B. Furthermore, PD-1 played various roles in phagocytosis in macrophages and microglia. Therefore, our results suggest that PD-1 signaling plays an important role in the regulation of macrophage/microglial polarization. Thus, deregulated PD-1 signaling may induce the polarization of macrophages/microglia toward the M1 phenotype. Overall, our results provide new insights into the modulatory mechanisms of macrophage/microglial polarization, thereby possibly facilitating the development of new therapies for SCI via the regulation of macrophage/microglial polarization through PD-1 signaling.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-013-0254-x) contains supplementary material, which is available to authorized users.
Highlights
The inflammatory response plays an important role in the pathogenesis of spinal cord injury (SCI) [1, 2]
We demonstrate that programmed death-1 (PD-1) deficiency in vitro regulates the M1/M2 polarization of macrophages/microglia via signal transducer and activator of transcription 1 (STAT1) or STAT6 phosphorylation, thereby playing opposing roles for phagocytosis in macrophages and microglia
The presence of PD-L1, but not PD-1, was observed in astrocytes around the lesion sites after SCI (Supplementary Fig. S1). These results suggest that both PD-1 and PD-L1 are upregulated after SCI
Summary
The inflammatory response plays an important role in the pathogenesis of spinal cord injury (SCI) [1, 2]. M1 macrophages/microglia produce high levels of proinflammatory cytokines, such as IL-12, IL-1β, and tumor necrosis factor alpha, in addition to increased levels of oxidative metabolites, such as inducible nitric oxide synthase (iNOS) [5, 6] These inflammatory factors are promoted by the IFN-γmediated signal transducer and activator of transcription 1 (STAT1) signaling pathway. M2 macrophages produce high levels of arginase 1 (Arg1), mannose receptor (CD206), IL-10, transforming growth factor beta (TGF-β), and several neurotrophic factors, such as ciliary neurotrophic factor, insulin-like growth factor, epidermal growth factor, and nerve growth factor, all of which suppress inflammatory responses and facilitate axonal regeneration These molecules are mediated by the STAT6 signaling pathway [3]. Inhibitory signals may prevent the overactivation of M1 macrophages/microglia after SCI [10,11,12]
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